Neurodegeneration can be produced by the accumulation of insoluble intraneuronal protein aggregates formed from Huntingtin and other CAG-repeat disease proteins, a-synuclein and tau protein. Tau mutations in frontal temporal dementias (FTD) such as p301L lead to tau aggregation and neuron death in transgenic modes. In Alzheimer's (AD), the relative roles and interrelationships between direct AB toxicity, tau and synuclein pathology, and neurodegeneration remain unclear. However, recent data from transgenics show that beta amyloid (AB) which causes AD, may induce CNS tau/tangle pathology. Our preliminary date indicate that compared to infusion of vehicle (HLD), low dose soluble AB oligomers infused into human tau transgenics with P301L transgene induces tau pathology, detergent insoluble phosphotau and neuron loss. The P301L mutation is associated with vulnerability to AB induced cognitive loss compared to human WT mice or Tg negative mice, a novel finding. This may involve oxidative damage and caspase and tau kinase activation. A major identified defense against toxicity from intracellular protein aggregates is the induction of heat shock proteins (HSPs) as part of the cellular stress response. HSP70 transgene overexpression protects against neurodegeneration in CAG repeat, synuclein aggregate and ischemia models, presumable because this pathway is needed to eliminate toxic aggregates of proteins. In this proposal we will examine the impact of soluble ABeta42 infusion on tau pathology, neurodegeneration (Aim 1) and cognitive deficits (Aim 2) in human WT, p301L and V337 genomic transgenic mice and test two putative protective agents with distinct mechanisms. We hypothesize that tau pathology endpoints will be partially ameliorated by inhibitors of caspase activation (Aim 3) and a major tau kinase, GSK3B (Aim 4)-but completely ameliorated by treatment with an NSAID/antioxidant (Aim 5) shown to be an effective potentiator of the CNS cellular stress response, notably HSP70. Our proposal will demonstrate AB42 oligomer-and tau-dependent intraneuronal ptau aggregate inclusions and neurodegeneration leading to severe cognitive deficits (a better AD model). Further, we anticipate that curcumin, an NSAID/antioxidant that potentiates HSP70 induction will prove more effective than GSK3B, Cox-2 inhibitors that block pERK or vitamin E in protecting against tau pathology and neurodegeneration in this model. Successful results may have profound implications for treatment of Alzheimer's and other inclusion-related neurodegenerative diseases.